Method and device for correcting optical signals

ABSTRACT

An optical device is used to monitor an implant embedded in the tissue of a mammal (e.g., under the skin). The implant receives excitation light from the optical device and emits light that is detected by the optical device, including an analyte-dependent optical signal. Scatter and absorption properties of tissue change over time due to changes in hydration, blood perfusion and oxygenation. The optical device has an arrangement of light sources, filters and detectors to transmit excitation light within excitation wavelength ranges and to measure emitted light within detection wavelengths. Changes in scattering and absorption of light in the tissue, such as diffuse reflectance, are monitored. The light sources, filters and detectors may also be used to monitor autofluorescence in the tissue to correct autofluorescence background.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/102,070, filed on Aug. 13, 2018, which is a divisional of U.S. patentapplication Ser. No. 14/199,497, filed on Mar. 6, 2014, which claims thebenefit of U.S. provisional patent application 61/785,087 filed on Mar.14, 2013, each of which is hereby incorporated by reference in itsentireties.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under grant numbers NIHR01 EB016414 and NIH R43 DK093139, awarded by the National Institutes ofHealth. The government has certain rights in the invention.

BACKGROUND

The invention relates to a method and device for monitoring an implant,and in particular to a method and device for correcting luminescentsignals emitted from the implant.

The monitoring of the level of analyte, such as glucose, lactate oroxygen, in certain individuals is important to their health. High or lowlevels of glucose, or other analytes, may have detrimental effects or beindicative of specific health states. The monitoring of glucose isparticularly important to individuals with diabetes, a subset of whommust determine when insulin is needed to reduce glucose levels in theirbodies or when additional glucose is needed to raise the level ofglucose in their bodies.

A conventional technique used by many individuals with diabetes forpersonally monitoring their blood glucose level includes the periodicdrawing of blood, the application of that blood to a test strip, and thedetermination of the blood glucose level using calorimetric,electrochemical, or photometric detection. This technique does notpermit continuous or automatic monitoring of glucose levels in the body,but typically must be performed manually on a periodic basis.Unfortunately, the consistency with which the level of glucose ischecked varies widely among individuals. Many people with diabetes findthe periodic testing inconvenient, and they sometimes forget to testtheir glucose level or do not have time for a proper test. In addition,some individuals wish to avoid the pain associated with the test.Unmonitored glucose may result in hyperglycemic or hypoglycemicepisodes. An implanted sensor that monitors the individual's analytelevels would enable individuals to monitor their glucose, or otheranalyte levels, more easily.

A variety of devices have been developed for monitoring of analytes(e.g., glucose) in the blood stream or interstitial fluid of varioustissues. A number of these devices use sensors that are inserted into ablood vessel or under the skin of a patient. These implanted sensors areoften difficult to read or to monitor optically, because of low levelsof florescence in the presence of high scatter due to dynamic changes inskin conditions (e.g., blood level and hydration). The skin is highlyscattering, and the scattering may dominate the optical propagation.Scatter is caused by index of refraction changes in the tissue, and themain components of scatter in the skin are due to lipids, collagen, andother biological components. The main absorption is caused by blood,melanin, water, and other components.

One device, disclosed in published US patent application 20090221891 toYu, includes components of an assay for glucose. An optical signal isread out transcutaneously by external optics when the sensor isimplanted in vivo. A fluorimeter separately measures, for a donorchromophore and an acceptor chromophore, an excitation light intensity,an ambient light intensity, and an intensity of combined luminescent andambient light. Measurements are taken by holding the fluorimeter closeto the skin and in alignment with the sensor. The final output providedis the normalized ratio between the luminescent intensity from the twofluorophores, which may be converted to analyte concentration usingcalibration data. A calibration curve is established empirically bymeasuring response versus glucose concentration. Although this deviceprovides some light signal correction, it may still be difficult toobtain accurate readings due to dynamic skin changes that cause opticalscattering and absorption of light emitted from the implant.

US patent application 20110028806 to Merritt discloses another procedureand system for measuring blood glucose levels. A set of photodiodesdetects the luminescence and reflectance of light energy emitted fromone or more emitters, such as LEDs, into a patient's skin. Smallmolecule metabolite reporters (SMMRs) that bind to glucose areintroduced to tissue of the stratum corneum and the epidermis to providemore easily detected luminescence. The test results are calibrated witha reflectance intensity measurement taken at approximately theexcitation wavelength. In addition, the method includes measuring asecond luminescence and reflectance intensity to normalize data from thefirst set of measurements. First luminescence and reflectance intensitymeasurements are taken at a site treated with an SMMR. Secondluminescence and reflectance intensity measurements are taken at anuntreated, background site. The background measurement is then used tocorrect for the background tissue luminescence and absorption through awavelength normalization. Although this method provides some lightsignal correction for background luminescence and reflectance, it maystill be difficult to obtain accurate and/or consistent glucose readingsfrom glucose-binding molecules in the epidermis.

There is still a need for a small, compact device that can accuratelyand consistently monitor an implanted sensor and provide signals to ananalyzer without substantially restricting the movements and activitiesof a patient. Continuous and/or automatic monitoring of the analyte canprovide a warning to the patient when the level of the analyte is at ornear a threshold level. For example, if glucose is the analyte, then themonitoring device might be configured to warn the patient of current orimpending hyperglycemia or hypoglycemia. The patient can then takeappropriate actions.

SUMMARY

According to one aspect, a method is provided for correcting at leastone analyte-dependent optical signal emitted from an implant. Theimplant is typically embedded in tissue of a mammalian body. The implantis capable of emitting, in response to excitation light within anexcitation wavelength range, the analyte-dependent optical signal withinan emission wavelength range. The method comprises transmitting firstexcitation light within the excitation wavelength range through thetissue to the implant and measuring a first optical signal emitted fromthe tissue, within the emission wavelength range, in response to thefirst excitation light. The method also comprises transmitting secondexcitation light within the emission wavelength range into the tissueand measuring a second optical signal emitted from the tissue, withinthe emission wavelength range, in response to the second excitationlight. At least one corrected signal value is calculated in dependenceupon the measured signals.

According to another aspect, an optical detection device is provided formonitoring an implant embedded in tissue of a mammalian body. Theimplant is capable of emitting, in response to excitation light withinan excitation wavelength range, at least one analyte-dependent opticalsignal within an emission wavelength range. The device comprises a firstlight source arranged to transmit first excitation light within theexcitation wavelength range through the tissue to the implant. A secondlight source is arranged to transmit second excitation light within theemission wavelength range into the tissue. At least one detector isarranged to measure, in response to the first excitation light, a firstoptical signal emitted from the tissue in the emission wavelength rangeand arranged to measure, in response to the second excitation light, asecond optical signal emitted from the tissue in the emission wavelengthrange.

According to another aspect, a method is provided for correcting atleast one analyte-dependent optical signal emitted from an implantembedded in tissue of a mammalian body. The implant is capable ofemitting, in response to excitation light within an excitationwavelength range, the analyte-dependent optical signal within anemission wavelength range. The method comprises transmitting firstexcitation light within the excitation wavelength range through thetissue to the implant and measuring a first optical signal emitted fromthe tissue, within the emission wavelength range, in response to thefirst excitation light. The method also comprises transmitting secondexcitation light within the excitation wavelength range into the tissueand measuring a second optical signal emitted from the tissue, withinthe emission wavelength range, in response to the second excitationlight. The second excitation light and the light emitted in response tothe second excitation light form a light path that is spaced laterallyfrom the implant a sufficient distance to avoid significant contributionfrom implant reporters (e.g., luminescent, luminescent, bioluminescent,or phosphorescent reporters). At least one corrected signal value iscalculated in dependence upon the measured optical signals.

According to another aspect, an optical detection device is provided formonitoring an implant embedded in tissue of a mammalian body. Theimplant is capable of emitting, in response to excitation light withinan excitation wavelength range, at least one analyte-dependent opticalsignal within an emission wavelength range. The device comprises a firstlight source arranged to transmit first excitation light in theexcitation wavelength range through the tissue to the implant. A firstdetector is arranged to measure, in response to the first excitationlight, a first optical signal emitted from the tissue in the emissionwavelength range. A second light source is arranged to transmit secondexcitation light within the excitation wavelength range into the tissue.A second detector is arranged to measure, in response to the secondexcitation light, a second optical emitted from the tissue in theemission wavelength range. The second light source and the seconddetector are positioned with respect to each other such that the secondexcitation light and the light emitted in response to the secondexcitation light form a light path that is spaced laterally from theimplant a sufficient distance to avoid significant contribution fromimplant reporters.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing aspects and advantages of the present invention willbecome better understood upon reading the following detailed descriptionand upon reference to the drawings where:

FIG. 1 shows a schematic side view of an optical detection device formonitoring an implant according to one embodiment of the invention.

FIG. 2 shows a schematic side view of an optical detection device formonitoring an implant according to another embodiment of the invention.

FIG. 3 shows a schematic side view of aspects of an optical detectiondevice according to another embodiment of the invention.

FIG. 4 shows a schematic plan view of an optical detection deviceaccording to another embodiment of the invention.

FIG. 5 shows a schematic cross-sectional view of the device of FIG. 4.

FIG. 6 shows a schematic side view of an optical detection deviceaccording to some embodiments of the invention.

FIG. 7 shows a schematic plan view of an optical detection deviceaccording to some embodiments of the invention.

FIG. 8 shows a schematic cross-sectional view of the device of FIG. 7.

FIG. 9 shows a schematic plan view of an optical detection deviceaccording to some embodiments of the invention.

FIG. 10 shows a schematic cross-sectional view of the device of FIG. 9.

FIG. 11 shows a schematic plan view of an optical detection deviceaccording to some embodiments of the invention.

FIG. 12 shows a schematic, exploded view of the device of FIG. 11.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In the following description, it is understood that all recitedconnections between structures can be direct operative connections orindirect operative connections through intermediary structures. A set ofelements includes one or more elements. Any recitation of an element isunderstood to refer to at least one element. A plurality of elementsincludes at least two elements. Unless otherwise required, any describedmethod steps need not be necessarily performed in a particularillustrated order. A first element (e.g. data) derived from a secondelement encompasses a first element equal to the second element, as wellas a first element generated by processing the second element andoptionally other data Making a determination or decision according to aparameter encompasses making the determination or decision according tothe parameter and optionally according to other data. Unless otherwisespecified, an indicator of some quantity/data may be the quantity/dataitself, or an indicator different from the quantity/data itself.Computer programs described in some embodiments of the present inventionmay be stand-alone software entities or sub-entities (e.g., subroutines,code objects) of other computer programs. Computer readable mediaencompass non-transitory media such as magnetic, optic, andsemiconductor storage media (e.g. hard drives, optical disks, flashmemory, DRAM), as well as communications links such as conductive cablesand fiber optic links. According to some embodiments, the presentinvention provides, inter alia, computer systems comprising hardware(e.g. one or more processors and associated memory) programmed toperform the methods described herein, as well as computer-readable mediaencoding instructions to perform the methods described herein.

The following description illustrates embodiments of the invention byway of example and not necessarily by way of limitation.

FIG. 1 shows a schematic side view of an optical detection device 10 formonitoring an implanted sensor or implant 12, according to a firstembodiment of the invention. The implant 12 is embedded in tissue of amammalian body (which may be a portion of tissue that is attached orunattached to the rest of the body in various embodiments). The implant12 is typically embedded under a surface of skin 14. The implant 12 isembedded at a first depth under the surface of the skin 14, which ispreferably a sufficient depth to position the implant in thesubcutaneous tissue (e.g., in the range of 1 to 5 mm under the surfaceof the skin 14). In some embodiments, the implant 12 is embedded in thetissue at a depth greater than or equal to 2 mm under the surface of theskin 14, and in other embodiments the implant 12 is embedded in thetissue at a depth greater than or equal to 4 mm under the surface of theskin.

The implant 12 is capable of emitting, in response to excitation lightwithin an excitation wavelength range, at least one analyte-dependentoptical signal within an emission wavelength range. The analyte maycomprise, for example, glucose or other analytes in the body of theindividual. Suitable optical signals include, but are not limited, toluminescent, luminescent, bioluminescent, phosphorescent,autoluminescence, and diffuse reflectance signals. In preferredembodiments, the implant 12 contains one or more luminescent dyes whoseluminescence emission intensity varies in dependence upon the amount orpresence of target analyte in the body of the individual.

A first light source 16 is arranged to transmit first excitation lightwithin the excitation wavelength range from the surface of the skin 14to the implant 12. A second light source 18 is arranged to transmitsecond excitation light from the surface of the skin 14 into the tissue15. The second excitation light is preferably within the emissionwavelength range of the analyte-dependent luminescent signal (e.g., theemission peak). Suitable light sources include, without limitation,lasers, semi-conductor lasers, light emitting diodes (LEDs), organicLEDs.

At least one detector, and more preferably at least two detectors 20, 22are arranged with the light sources 16, 18. The first detector 20 ispositioned to measure, in response to the first excitation light fromthe first light source 16, a first optical signal (e.g., the intensityof light) emitted at the surface of the skin 14 within the emissionwavelength range. The detector 20 is also arranged to measure, inresponse to the second excitation light, a second optical signal emittedfrom the tissue 15 through the surface of the skin 14 within theemission wavelength range. Suitable detectors include, withoutlimitation, photodiodes or CCDs. Although multiple detectors arepreferred for some embodiments, one could use a single universaldetector. The detectors 20, 22 are preferably filtered (e.g., dichroicfilters or other suitable filters) to measure the optical signalsemitted within respective wavelength ranges. In this example, a suitableluminescent dye sensitive to glucose concentration is Alexa 647responsive to excitation light (absorption) in the range of about 600 to650 nm (absorption peak 647 nm) and within an emission wavelength rangeof about 670 to 750 nm with an emission peak of about 680 nm.

In the operation of device 10, an analyte-dependent luminescent signalemitted from the implant 12 is corrected for diffuse reflectance and/orautofluorescence. The light source 16 is activated to transmit firstexcitation light within the excitation wavelength range from the surfaceof the skin 14 to the implant 12. The first detector 20 measures, inresponse to the first excitation light, a first optical signal emittedfrom the tissue 15 at the surface of the skin 14 within the emissionwavelength range, as represented by a first light path 24 from the lightsource 16 to the implant 12 to the first detector 20. The light path 24provides the primary analyte-dependent optical signal. The second lightsource 18 is activated to transmit second excitation light from thesurface of the skin 14 to a second depth in the tissue 15 under thesurface of the skin 14. The second excitation light is substantiallywithin the emission wavelength range (e.g., the emission peak) of theanalyte-dependent luminescent signal. The first detector 20 measures, inresponse to the second excitation light, a second optical signal emittedfrom the tissue 15 through the surface of the skin 14 within theemission wavelength range, as represented by a second light path 26.

The second optical signal may be used as a reference signal to correctthe primary analyte-dependent optical signal for diffuse reflectance orscattering of light in the tissue 15. In some embodiments, the seconddepth to which the light path 26 extends below the surface of the skin14 may be substantially equal to the first depth at which the implant 12is embedded (e.g., in the subcutaneous tissue at a depth of 1 to 5 mmunder the surface of the skin 14). In some embodiments, the light path26 for the second optical signal extends to a depth greater than orequal to 2 mm under the surface of the skin 14, and in other embodimentsthe light path 26 for the second optical signal extends to a depthgreater than or equal to 4 mm under the surface of the skin.

An additional correction factor may optionally be obtained by activatingthe first light source 16 to transmit third excitation light, within theexcitation wavelength range, from the surface of the skin 14 to a thirddepth in the tissue 15. In some embodiments, the third depth may differfrom the first and second depths, and the third depth may be in therange of 1 to 5 mm under the surface of the skin 14. The second detector22 measures a third optical signal emitted from the tissue 15 throughthe surface of the skin 14 within the excitation wavelength range inresponse to the third excitation light, as represented by a third lightpath 28. At least one corrected signal value is calculated in dependenceupon the measured optical signals. In one example, the primaryanalyte-dependent signal from the implant may be corrected as:

Corrected Signal=S(LS1, D1)*C(LS2, D1)*C(LS1, D2)   (1)

In equation (1) above, the term S(LS1, D1) represents the first opticalsignal, which is the primary analyte-dependent optical signal measuredfrom the first light path 24 from the first light source 16 to theimplant 12 to the first detector 20. The term C(LS2, D1) represents thesecond optical signal, which is a correction factor signal measured fromthe second light path 26 from the second light source 18 to the firstdetector 20. The term C(LS1, D2) represents an optional third opticalsignal, which is an additional correction factor signal measured fromthe third light path 28 from the first light source 16 to the seconddetector 22.

Thus, the primary analyte-dependent optical signal emitted from theimplant 12 may be corrected for diffuse reflectance or scattering withinthe emission wavelength range of the analyte-dependent optical signal,to account for optical scattering or absorption of the signal in thetissue 15. The analyte-dependent optical signal may optionally becorrected for scattering, reflectance or attenuation in the excitationwavelength range to account for dynamic changes in skin properties. Oneadvantage of correcting the analyte-dependent signal by one or morereference signals is that accurate and/or consistent glucose values maybe determined from measurements of light emitted from an implant locatedrelatively deep in the tissue, such as in the subcutaneous region. Lightemitted from the implant 12 may be strongly modulated by the tissue 15between the implant and the surface of the skin 14. Embodiments of thepresent invention provide means to correct for modulation of lightemitted from the tissue 15, in addition to correction for excitationlight and background or ambient light, if desired.

Another advantage is that measurements of the reference optical signalsused for correction factors (such as diffuse reflectance,autofluorescence, and/or background light) are taken in the same regionof tissue 15 in which the implant 12 is embedded in a few seconds oftime or less, so that dynamic skin or tissue properties, that may varywithin different regions of the body, are substantially the same for thecorrection signals as they are for the primary analyte dependent signalat the time of measurement. Prior to executing optical reads for theanalyte-dependent signal, the diffuse reflectance correction signaland/or the autofluorescence correction signal, a dark reading may betaken to account for background or ambient light, and this reading maybe used to further correct the signals, e.g., by background subtraction.A preferred order of optical readings for the correction factors isbackground subtraction, autofluorescence correction, and diffusereflectance correction, although no particular order is required.

In some embodiments, an analyte concentration (e.g., glucose level) isdetermined from the corrected signal value. Preferably a look-up tableor calibration curve is used to determine the analyte concentration independence upon the corrected signal value. The look-up table orcalibration curve may be in a microprocessor included with the optics.In some embodiments, the microprocessor is programmed to store measuredsignal values and/or to calculate corrected signal values.Alternatively, these functions may be performed in a separate processoror external computer in communication with the optical device. Theexternal processor or computer receives data representative of themeasured optical signals and calculates the corrected signal value andanalyte concentration. Alternatively, multiple processors may beprovided, e.g., providing one or more processors in the optical devicethat communicate (wirelessly or with wires) with one or more externalprocessors or computers.

FIG. 2 shows another embodiment of an optical detection device 30 formonitoring an implant 12. In this embodiment, the implant 12 is furthercapable of emitting, in response to excitation light within a secondexcitation wavelength range (that may share or overlap the firstemission wavelength range) at least one analyte-independent opticalsignal within a second emission wavelength range. The implant 12preferably contains an analyte-independent luminescence dye thatfunctions to control for non-analyte physical or chemical effects on areporter dye (e.g., photo bleaching or pH). Multiple dyes may used. Theanalyte-independent optical signal is not modulated by analyte presentin the tissue 15 and provides data for normalization, offsetcorrections, or internal calibration. The analyte-independent signal maycompensate for non-analyte affects that are chemical or physiological(e.g., oxygen, pH, redox conditions) or optical (e.g., water, lightabsorbing/scattering compounds, hemoglobin). Alternatively, theanalyte-independent signal may be provided by a stable reference dye inthe implant 12. Suitable stable reference materials include, but are notlimited to, lanthanide doped crystals, lanthanide doped nanoparticles,quantum dots, chelated lanthanide dyes, and metal (e.g., gold or silver)nanoparticles. The stable reference dye may provide a reference signalfor other signals (e.g., to determine photo bleaching).

The second embodiment differs from the first embodiment described abovein that the device 30 includes a third light source 40 for transmittingexcitation light into the tissue 15 through the surface of the skin 14.In the operation of device 30, an analyte-dependent luminescent signalemitted from the implant 12 is corrected using three reference signals.The first light source 32 is activated to transmit excitation lightwithin a first excitation wavelength range from the surface of the skin14, through the tissue 15, to the implant 12. The first detector 34measures, in response to the first excitation light, a first opticalsignal emitted from the tissue 15 at the surface of the skin 14 within afirst emission wavelength range, as represented by a first light path 42from the first light source 32, to the implant 12, and to the firstdetector 34. This first optical signal is the primary analyte-dependentoptical signal.

The second light source 38 is activated to transmit second excitationlight from the surface of the skin 14 to a second depth in the tissue15. The second excitation light is preferably within the first emissionwavelength range (e.g., the emission peak) of the primary analytedependent optical signal. The first detector 34 measures, in response tothe second excitation light, a second optical signal emitted from thetissue 15 at the surface of the skin 14 within the emission wavelengthrange, as represented by a second light path 44. The second opticalsignal may be used to correct for diffuse reflectance or scattering oflight in the tissue 15 between the implant 12 and the surface of theskin 14. In some embodiments, the depth of the second light path 44 maybe substantially equal to the first depth at which the implant 12 isembedded (preferably in the subcutaneous tissue 1 to 5 mm under thesurface of the skin 14). In some embodiments, the light path 44 for thesecond optical signal extends to a depth greater than or equal to 2 mmunder the surface of the skin 14, and in other embodiments the lightpath 44 for the second optical signal extends to a depth greater than orequal to 4 mm under the surface of the skin.

Next, the light source 38 is activated to transmit third excitationlight in the second excitation wavelength range from the surface of theskin 14 to the implant 12. The second detector 36 measures, in responseto the third excitation light, a third optical signal emitted from thetissue 15 at the surface of the skin 14 within the second emissionwavelength range, as represented by a third light path 46. In thisembodiment, the third optical signal is the analyte-independentluminescent signal. Next, the third light source 40 is activated totransmit fourth excitation light from the surface of the skin 14 intothe tissue 15. The fourth excitation light is preferably within theemission wavelength range of the analyte-independent luminescent signal.The detector 36 measures, in response to the fourth excitation light, afourth optical signal emitted from the tissue 15 at the surface of theskin 14 within this emission wavelength range, as represented by afourth light path 48. At least one corrected signal value is calculatedin dependence upon the measured optical signals. In one example, theprimary analyte-dependent signal from the implant 12 may be correctedas:

Corrected Signal=S(LS1, D1)*C(LS2, D1)/[S(LS2, D2)*C(LS3, D2)]  (2)

In equation (2) above, the term S(LS1, D1) represents the first opticalsignal which is the primary analyte-dependent signal measured from thefirst light path 42 from the first light source 32 to the implant 12 tothe first detector 34. The term C(LS2, D1) represents the second opticalsignal, which is a correction factor signal measured from the secondlight path 44 from the second light source 38 to the first detector 34.The term S(LS2, D2) represents the third optical signal, which is theanalyte-independent signal measured from the third light path 46extending from the second light source 38 to the implant 12 to thesecond detector 36. The term C(LS3, D2) represents the fourth opticalsignal, which is a correction factor signal measured from the fourthlight path 48 extending from the third light source 40 to the seconddetector 36.

In some embodiments in which two implant reporters (e.g., luminescentdyes) are utilized, it is possible that the implant reporters may shareor overlap excitation (absorption) or emission wavelength ranges. Forexample, in the embodiment of FIG. 2, the emission wavelength range ofthe first dye, which provides the analyte-dependent luminescence signal,shares or overlaps the excitation wavelength range of the second dye,which provides the analyte-independent luminescence signal In anotherembodiment, the first and second dyes may share or overlap excitationwavelength ranges (so that a common light source may be used) and emitoptical signals within different emission wavelength ranges. In anotherembodiment, the first and second dyes may be excited by light withindifferent excitation wavelength ranges and emit optical signals withinthe same or overlapping emission wavelength range(s).

FIG. 3 shows optical interrogation at different depths D2, D3, D4 in thetissue 15 relative to the first depth D1 of the implant 12 under thesurface of the skin 14. The spacing distances S1, S2, S3 between thearrangement of detectors 52, 54, 56 and the light source 50 determinesthe depths D2, D3, D4 of the respective light paths. In someembodiments, readings for optical signal corrections are performed atmultiple depths, as represented by the respective light paths, and themeasured values of the reference optical signals used for correction areaveraged for the correction factor. In some embodiments, the light pathfor the reference optical signal extends to a depth D2 in the tissue 15that is greater than the depth D1 at which the implant 12 is embedded.The light path for the reference optical signal may also extend to adepth D3 in the tissue 15 such that the light path passes through theimplant 12.

When the optical device has multiple possible combinations of spacingdistances between the light sources and detectors as shown in FIGS. 3-9,implementation may be more flexible, because the depth of the implant 12may be application-specific. In one embodiment, at least oneanalyte-independent signal, which may be emitted by the stable referencedye, is used to determine the appropriate depth for the light path(s)and resulting optical signal(s) measured to correct theanalyte-dependent signal for diffuse reflectance and/orautofluorescence. Preferably a look-up table is used to determine, basedon the measured intensity of the analyte-independent luminescent signalemitted from the implant, which of the possible depth(s) fornormalization optical signals should be used, or more specifically whichlight source/detector pairing(s). The look-up table may be in amicroprocessor included with the optical device, or in a separateprocessor or external computer in communication with the optical devicethat receives data representative of the measured optical signals (e.g.,intensities of light measured within selected wavelengths).

In some embodiments, the processor is programmed to determine (e.g., bycalculation or a look-up table) a quantity or weight assigned tomeasurements of one or more diffuse reflectance signals. The quantity orweight assigned to the measured diffuse reflectance signal may then beused in correcting or normalizing one or more implant reporter signals(e.g., the primary analyte-dependent signal emitted from the implant) tocalculate the corrected signal value. The quantity or weight ispreferably determined in dependence upon the intensity of ananalyte-independent optical signal (e.g., from the stable referencedye). The intensity of the analyte-independent optical signal may varywith the depth of the implant in the tissue. For example, if the implantis embedded in tissue at a depth of 2 mm under the surface of the skin,the amount of light attenuation in the tissue will likely be less thanif the implant were embedded at a depth of 4 mm Reporter optical signalsemitted from a shallower implant may require less of a correction factorfor diffuse reflectance and/or autofluoresence than those signalsemitted from an implant embedded at a greater depth. In someembodiments, the diffuse reflectance correction factor used to corrector normalize the analyte-dependent signal is proportional to depth, andthe quantity or weight assigned to the diffuse reflectance measurementis determined in dependence upon the measurement of theanalyte-independent signal.

FIG. 4 shows another embodiment of an optical device 60 havingadditional light sources and detectors with multiple possiblecombinations of spacing distances between the light sources anddetectors. The light sources and detectors are arranged in a sensorpatch 62 adapted to be placed on the surface of the skin, and describedin greater detail below. At least one, and more preferably three centralexciter light sources 64A, 64B, and 64C are positioned to transmitexcitation light through a central via 66 in the patch 62. The centralvia 66 may contain one or more optical waveguide(s). At least onedetector, and more preferably an inner ring of three central detectors68A, 68B, and 68C are arranged around the central via 66. There is alsopreferably an outer ring 70 having multiple outer-ring exciter lightsources and outer-ring detectors (in this example twenty-five outer-ringlight sources and detectors) arranged in a substantially ring-shapedpattern, providing many permutations of possible optical channels. Thecombination of an excitation light source and a detection band is anoptical channel An example of one possible implementation of the opticaldevice 60 will now be given with reference to FIGS. 4-11 and Table 1,describing twelve optical channels.

TABLE 1 Optical Emissions Channel Function Excitation Detected ExciterDetector Comments 1 Implant Excitation Peak Emission Peak CentralCentral Analyte- Reporter 1 Reporter 1 Reporter 1 Exciter 1 Detector 1dependent 1 2 Implant Excitation Peak Emission Peak Central CentralAnalyte- Reporter 2 Reporter 2 Reporter 2 Exciter 2 Detector 2independent 1 3 Implant Excitation Peak Emission Peak Central CentralStable Reference Reporter 3 Reporter 3 Reporter 3 Exciter 3 Detector 3dye 4 Exciter Power Excitation Peak Excitation Peak Central Outer PowerNormalization Reporter 1 Reporter 1 Exciter 1 Detector 6 Normalization 15 Exciter Power Excitation Peak Excitation Peak Central Outer PowerNormalization Reporter 2 Reporter 2 Exciter 2 Detector 6 Normalization 26 Exciter Power Excitation Peak Excitation Peak Central Outer PowerNormalization Reporter 3 Reporter 3 Exciter 3 Detector 6 Normalization 37 Diffuse Emission Peak Emission Peak Outer Outer Diffuse Reflectance 1Reporter 1 Reporter 1 Exciter 6 Detector 6 Reflectance Data 8 DiffuseEmission Peak Emission Peak Outer Outer Diffuse Reflectance 2 Reporter 2Reporter 1 Exciter 7 Detector 6 Reflectance Data 9 Diffuse Emission PeakEmission Peak Outer Outer Diffuse Reflectance 3 Reporter 3 Reporter 1Exciter 8 Detector 6 Reflectance Data 10 Autofluorescence 1 ExcitationPeak Emission Peak Outer Outer Autofluorescence Reporter 1 Reporter 1Exciter 1 Detector 1 and ambient light 11 Autofluorescence2 ExcitationPeak Emission Peak Outer Outer Autofluorescence Reporter 2 Reporter 2Exciter 2 Detector 2 and ambient light 12 Autofluorescence3 ExcitationPeak Emission Peak Outer Outer Autofluorescence Reporter 3 Reporter 3Exciter 3 Detector 3 and ambient light

As shown in Table 1, optical channels 1-3 function to measure threereporter dye signals from the implant, including an analyte-specificsignal, an analyte-independent signal, and a stable reference dyesignal. Optical channel 1 functions to measure an analyte-specificluminescent signal from the implant, such as a light signal whoseintensity varies with glucose level. Other embodiments may includemultiple analyte-dependent signals from the implant. Optical channel 2functions to measure an analyte-independent control for non-analytephysical or chemical effects on the reporter dyes (e.g., photobleaching, pH,). Optical channel 3 functions to measure a stablereference dye (e.g., lanthanide).

As listed in Table 1 and shown in FIG. 4, each of the optical channels1-3 comprises a respective pairing of one of the three central exciterlight sources 64A, 64B, and 64C with a corresponding one of the threecentral detectors 68A, 68B, and 68C. FIG. 6 shows a schematic side viewof the light paths for optical detection of the implant reporters.Excitation light is transmitted through the central via 66 (whichpreferably contains a monolithic waveguide) from the surface of the skin14, through the tissue 15, and to the implant 12. Central detectors 68A,68B, and 68C measure, in response to the excitation light, opticalsignals emitted from the tissue 15 at the surface of the skin 14 inrespective emission wavelength ranges.

A suitable dye for the analyte-dependent signal is Alexa 647 which isresponsive to excitation light within an excitation wavelength range ofabout 600 to 650 nm (excitation peak 647 nm) and within an emissionwavelength range of about 670 to 750 nm with an emission peak of about680 nm A suitable dye for the analyte-independent signal is Alexa 750which is responsive to excitation light within an excitation wavelengthrange of about 700 to 760 nm (excitation peak 750 nm) and within anemission wavelength range of about 770 to 850 nm with an emission peakof about 780 nm A suitable stable reference dye is erbium with a firstexcitation light wavelength range of about 650 to 670 nm (excitationpeak about 650 nm), a second excitation wavelength range of about 800 to815 nm (with an excitation peak of about 805 nm), and an emissionwavelength range of about 980 to 1050 nm (emission peak of about 1020nm). In another embodiment, erbium an Alexa 647 may be excited from thesame light source, which has the advantage that an optional step ofpower normalization between multiple light sources is reduced oreliminated.

Referring again to Table 1, optical channels 4-6 provide exciter powernormalization signals, which are preferred in embodiments where morethan one light source is used. The exciter power normalization signalsare used to normalize differences in the power of excitation lightoutput by each light source, which output power may vary slightly foreach light source. As shown in FIGS. 4-5, the attenuation of excitationlight traveling from central via 66 to outer ring 70 is measured,reducing or eliminating contribution by reporters (e.g., fluorophores)of the implant 12. The optical channels 4-6 comprise three combinationsof pairings of the three central exciter light sources 64A, 64B, and 64Cwith outer-ring detector 6. Alternatively, multiple detectors may beused to detect the intensity of exciter power normalization signals,preferably outer-ring detectors. For exciter power normalizationsignals, excitation light within the excitation wavelength range of animplant reporter is transmitted into the tissue 15. An optical signalemitted from the tissue 15 within the excitation wavelength range ismeasured by the detector 6. The corrected signal value for an implantreporter may be normalized for exciter power of a respective lightsource, e.g., by dividing the optical signal measured for the reporterby the measured intensity of the excitation light within the excitationwavelength range.

Optical channels 7-9 (Table 1) provide diffuse reflectance measurementsto correct the luminescent dye reporter signals from the implant. Asshown in FIGS. 7-8, outer detector 6 measures attenuation by tissue 15of light signals in the emission wavelength ranges of the luminescentreporter dyes of the implant 12. Optical channels 7-9 comprise three ofthe outer exciter light sources 71A, 71B, and 71C arranged in outsidering 70, each paired with the detector 6 in this example, and preferablypositioned to provide a range of distances between each lightsource/detector combination, to compute diffuse reflectance correctionvalues for each luminescent reporter dye of the implant 12. Rather thanemploying the detector 6 to measure all three optical signals, multipledetectors may be used in alternative embodiments.

Optical channels 10-12 (Table 1) provide measurements ofautofluorescence and ambient light to correct the luminescent dyereporter signals from the implant. As shown in FIGS. 9-10, opticalchannels 10-12 comprise three pairs 73A, 73B, and 73C of the outerexciter light sources and outer-ring detectors arranged in the outsidering 70. The three pairs 73A, 73B, and 73C of the outer exciter lightsources and outer detectors provide the same excitation and emissionspectra of the three reporter luminescent dyes of the implant 12, andare located on outer ring 70 away from implant 12. In particular, eachpair of outer exciter light source/detector for the autofluorescencemeasurement(s) are positioned with respect to each other such that theexcitation light and the light emitted in response to the excitationlight form a light path 78 that is spaced laterally from the implant 12a sufficient distance to avoid significant contribution from implantfluorophores.

It is preferred that the lateral spacing S4 be greater than or equal to0.25 cm, more preferably greater than 0.5 cm, and most preferablygreater than 1 cm. It is also preferred that the depth of the light path78 extend about 1 to 5 mm into the tissue 15 under the surface of theskin 14. When multiple pairs are used, each light path may havesubstantially the same depth or different depths, and the measuredintensities of the autofluorescence optical signals may be averaged toobtain a correction factor. It is preferred that the contribution fromthe implant reporter(s) (e.g., fluorophores) to the autofluorescencemeasurement be less than 30% of the measured intensity, more preferablyless than 20%, an most preferably less than 10%.

FIG. 11 shows a plan view of the sensor patch 62 having central via 66for excitation light. Preferred dimensions of patch 62 may be, forexample, a diameter of about 16 mm and a thickness T of about 1.6 mm.FIG. 12 shows a schematic, exploded view of the patch 62 comprisingmultiple layers in a stack. In some embodiments, the layers may comprisea plastic cover 80 having a preferred thickness of about 200 um, a lightcontrol film 82 having a preferred thickness of about 100 um, a filter84 having a preferred thickness of about 200 um, another light controlfilm 86 having a preferred thickness of about 100 um, a silicon layer 88having a preferred thickness of about 200 um, a printed circuit board(PCB) 90 having a preferred thickness of about 400 um, a battery 92having a preferred thickness of about 300 um, and a case 94 having athickness of about 200 um. The PCB 90 may include a microprocessor thatis programmed to store measured values and/or to calculate the correctedsignal values as previously described. The light control film is a lensarray with an aperture array on its back side.

It should be clear to one skilled in the art that embodiments of thedescribed invention may include cabled or wireless hand-held readers,wireless skin patch readers, bench-top instruments, imaging systems,handheld devices (e.g., cell phones or mobile communication devices),smartphone attachments and applications, or any other configuration thatutilizes the disclosed optics and algorithms.

Tissue optical heterogeneity in some cases may be significant. Thus, itmay be advantageous to utilize a single light source and a singledetector to assure that every color passes through the same opticalpathway through the tissue. In one embodiment, a light source can bepositioned with a set of moveable filters between the light source andthe surface of the skin Similarly a single photodetector can be utilizedin place of separate discrete detector elements. The detector may beused to detect different colors by using moveable or changeable filtersto enable multiple wavelengths to be measured. Changing or movingfilters may be accomplished by a mechanical actuator controlling arotating disc, filter strip or other means. Alternatively, opticalfilters may be coated with a material that when subjected to current,potential, temperature or another controllable influence, will changeoptical filtering properties, so that a single photodetector can serveto detect multiple colors.

It will be clear to one skilled in the art that the above embodimentsmay be altered in many ways without departing from the scope of theinvention. For example, many different permutations or arrangements ofone or more light sources, one or more detectors, filters, and/or fibersconnecting the optical components may be used to realize the device andmethod of the invention. For example, in some embodiments the lightsources and detectors are arranged with optical fibers or cables totransmit excitation light into the skin and measure optical signalsemitted from the skin, without having to position the light sources anddetectors directly on the skin of an individual. Presently preferredvalues for dimensions of the device and/or wavelength ranges may differin alternative embodiments. Accordingly, the scope of the inventionshould be determined by the following claims and their legalequivalents.

1. (canceled)
 2. A device, comprising: a housing; a first light sourcedisposed within the housing and configured to emit a first opticalsignal with a predefined excitation wavelength into tissue containing animplanted sensor that is configured to emit an analyte-dependent opticalsignal with a predefined emission wavelength in response to beingilluminated with the first optical signal, the predefined emissionwavelength different from the predefined excitation wavelength; a secondlight source disposed within the housing and configured to emit a secondoptical signal with the predefined emission wavelength into the tissue;and at least one detector disposed within the housing and configured toreceive the analyte-dependent optical signal and backscatter from thesecond optical signal.
 3. The device of claim 2, wherein the at leastone detector is configured to receive backscatter from the secondoptical signal in the emission wavelength range.
 4. The device of claim2, further comprising a processor configured to: receive, from the atleast one detector, data representative of the analyte-dependent opticalsignal and data representative of backscatter from the second opticalsignal, calculate a correction factor based on the data representativeof backscatter from the second optical signal, and calculate at leastone of a quantity or a concentration of analyte by applying thecorrection factor to the data representative of the analyte-dependentoptical signal.
 5. The device of claim 2, wherein the at least onedetector is configured to receive an analyte-independent signal emittedby the implanted sensor in response to the implanted sensor beingilluminated by the first optical signal, the sensor reader furthercomprising a processor configured to: receive, from the at least onedetector, data from the at least one detector representative of theanalyte-dependent optical signal, data representative of backscatterfrom the second optical signal, and data representative of ananalyte-independent optical signal emitted from the implant, calculate acorrection factor using at least one of the data representative ofbackscatter from the second optical signal or the data representative ofthe analyte-independent optical signal, and calculate at least one of aquantity or a concentration of analyte by applying the correction factorto the data representative of the analyte-dependent optical signal. 6.The device of claim 2, further comprising: a third light sourceconfigured to emit a third optical signal with the predefined excitationwavelength into the tissue, the third light source spaced apart from thefirst light source such that only one of the first light source or thethird light source is configured to illuminate the implanted sensor at atime, the at least one detector configured to receive a fourth opticalsignal emitted from the tissue, the fourth optical signal being withinthe emission wavelength range and associated with tissueautofluorescence, the fourth optical signal not including a significantcontribution from the implanted sensor.
 7. The device of claim 2,further comprising a processor configured to: receive, from the at leastone detector, data representative of an analyte-independent opticalsignal, determine a depth of the implanted sensor based on the datarepresentative of the analyte-independent signal, receive, from the atleast one detector, data representative of backscatter from the secondoptical signal, calculate a correction factor based on the datarepresentative of backscatter, and calculate, at least one of a quantityor a concentration of analyte based on the data representative of ananalyte-independent optical signal, the depth of the implanted sensorand the data representative of backscatter.
 8. The device of claim 2,wherein: the predefined emission wavelength is a first predefinedemission wavelength; the predefined excitation wavelength is a firstpredefined excitation wavelength, the device further comprising: a thirdlight source disposed configured to emit a third optical signal with asecond pre-defined excitation wavelength to illuminate the implantedsensor, the implanted sensor configured to emit an analyte-independentoptical signal with a second pre-defined emission wavelength in responseto being illuminated by the third optical signal; and a fourth lightsource configured to emit a fourth optical signal with the secondpre-defined emission wavelength, the at least one detector configured toreceive the analyte-independent optical signal and backscatter from thefourth optical signal.
 10. The device of claim 2, wherein the firstlight source and the second light source are light emitting diodes. 11.A device, comprising: a housing; a first light source disposed withinthe housing and configured to emit a first optical signal with a firstpredefined excitation wavelength into tissue containing an implantedsensor that is configured to emit an analyte-dependent optical signalwith a first predefined emission wavelength in response to beingilluminated with the first optical signal, the first predefined emissionwavelength different from the first predefined excitation wavelength; asecond light source disposed within the housing and configured to emit asecond optical signal with a second predefined excitation wavelength,the implanted sensor configured to emit an analyte-independent opticalsignal with a second predefined emission wavelength in response to beingilluminated with the second optical signal, the second predefinedemission wavelength different from each of the first predefined emissionwavelength, the first predefined excitation wavelength, and the secondpredefined excitation wavelength; a third light source disposed withinthe housing and configured to emit a third optical signal with at leastone of the first predefined excitation wavelength or the secondpredefined excitation wavelength, the third light source spaced apartfrom the first light source and the second light source such that, whenthe first light source and the second light source illuminate theimplant, the third light source is positioned away from and is notconfigured to illuminate the implant; at least one detector disposedwithin the housing and configured to receive the analyte-dependentoptical signal, the analyte-independent optical signal, and a fourthoptical signal in response to the tissue being illuminated with thethird optical signal.
 12. The device of claim 11, wherein the thirdoptical signal has the first predefined excitation wavelength.
 13. Thedevice of claim 11, wherein the third optical signal has the secondpredefined excitation wavelength.
 14. The device of claim 11, whereinthe fourth optical signal includes at least one of backscatter from thethird optical signal or an autofluorescence signal associated withtissue being excited by the third optical signal.
 15. The device ofclaim 11, wherein the at least one detector includes: a first detectorconfigured to receive at least one of the analyte-dependent opticalsignal or the analyte-independent optical signal, and a second detectorconfigured to receive the fourth optical signal, the second detectorspaced apart from the first detector such that when the first lightsource and the second light source illuminate the detector, the thirdlight source and the third detector are configured to detect the fourthoptical signal and not light emitted from the implanted sensor.
 16. Thedevice of claim 11, further comprising: a printed circuit board, thefirst light source, the second light source, the third light source, andthe at least one detector coupled to the printed circuit board.
 17. Thedevice of claim 11, further comprising a processor configured to:receive, from the at least one detector, data representative of theanalyte-dependent optical signal, data representative of theanalyte-independent optical signal, and data representative of thefourth optical signal; calculate a correction factor based on at leastone of the analyte-independent optical signal or the fourth opticalsignal; and calculate at least one of a quantity or a concentration ofthe analyte by applying the correction factor to the data representativeof the analyte-dependent optical signal.
 18. The device of claim 11,further comprising a processor configured to: receive, from the at leastone detector, data representative of the analyte-dependent opticalsignal, data representative of the analyte-independent optical signal,and data representative of the fourth optical signal; calculate acorrection factor based on the analyte-independent optical signal andthe fourth optical signal; and calculate at least one of a quantity or aconcentration of the analyte by applying the correction factor to thedata representative of the analyte-dependent optical signal.
 19. Thedevice of claim 11, further comprising: a fourth light source disposedwithin the housing and configured to emit a fifth optical signal with awavelength of at least one of the analyte-dependent optical signal orthe analyte-independent optical signal, the detector configured toreceive backscatter from the fifth optical signal.
 20. The device ofclaim 19, further comprising a processor configured to: receive, fromthe at least one detector, data representative of the analyte-dependentoptical signal, data representative of the analyte-independent opticalsignal, and data representative of the fourth optical signal, and datarepresentative of backscatter from the fifth optical signal; calculate acorrection factor based, at least in part, on the fourth optical signaland backscatter from the fifth optical signal; and calculate at leastone of a quantity or a concentration of the analyte by applying thecorrection factor to the data representative of the analyte-dependentoptical signal.
 21. A method, comprising: illuminating an implantedsensor that is disposed within tissue with a first optical signal havingan excitation wavelength; detecting, an analyte-dependent optical signalfrom the implant in response to the implantable sensor being illuminatedwith the first optical signal, the analyte-dependent optical signalhaving an emission wavelength; illuminating the tissue with a secondoptical signal having the emission wavelength; detecting backscatter ofthe second optical signal; calculating a correction factor based on thebackscatter of the second optical signal; and calculating at least oneof a concentration or a quantity of an analyte by applying thecorrection factor to data associated with the analyte-dependent opticalsignal.